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Sacubitril/Valsartan: Effect on Walking Test and Physical Capability

Sgorbini L. · Rossetti A. · Galati A.

Author affiliations

Unit of Cardiac Rehabilitation, ASL RM 1, Villa Betania, Rome, Italy

Corresponding Author

Luca Sgorbini

Unit of Cardiac Rehabilitation, ASL RM 1

Villa Betania, Via Pio IV, 42

IT-00165 Rome (Italy)

E-Mail Sgorbini.luca@libero.it

Related Articles for ""

Cardiology 2017;138(suppl 1):17-20

Abstract

The 6-min walk test (6MWT) is a simple and inexpensive exercise test to evaluate physical functional capacity that is widely used in heart failure (HF) patients. With the 6MWT, a distance <350 m is associated with increased mortality in patients with HF, and change in walking distance >50 m is considered clinically relevant. To our knowledge, information on improvement in physical functional capacity with sacubitril/valsartan, as assessed by the 6MWT, is still scant. In our daily practice, we apply this test to all patients whenever possible; therefore, we report here the findings observed in a small series of 5 patients with HF with reduced ejection fraction after a 1-month treatment with sacubitril/valsartan at full dose. The mean distance walked on the 6MWT at baseline was 129 m (±64 SD), and this value increased to 436 m (±156) after 1 month of therapy with sacubitril/valsartan 97/103 mg b.i.d. The mean difference from baseline was 305 m (±110). According to these preliminary findings, in clinical practice, a 1-month therapy of sacubitril/valsartan optimized at a 97/103-mg b.i.d. dose appears to be associated with a relevant improvement in the 6MWT.

© 2017 S. Karger AG, Basel


Introduction

Sacubitril/valsartan (LCZ696, Entresto; Novartis, Basel, Switzerland) is the first molecule belonging to angiotensin receptor-neprilysin inhibitors (ARNi). Indeed, it exerts a dual action: valsartan blocks the angiotensin II receptor while sacubitril inhibits neprilysin, an endopeptidase which cleaves natriuretic peptides [1]. Sacubitril/valsartan was effective in patients with HF with reduced ejection fraction (HFrEF) in the pivotal randomized PARADIGM-HF trial and in the preliminary analysis of the ongoing PARAGON-HF trial [2,3]. Given its demonstrated efficacy in robust studies, the recent European Society of Cardiology (ESC) guidelines recommend the use of ARNi instead of ACE inhibitors for the treatment of HFrEF [4]. Due to its recent introduction in HF therapeutic clinical management, evidence from “field practice” experience appears necessary to improve the clinical management of patients treated with sacubitril/valsartan.

The 6-min walk test (6MWT) is a simple and inexpensive submaximal exercise test able to evaluate physical functional capacity, which is widely used for the clinical assessment of HF patients [5,6,7]. This test reproduces the activities of daily life: this is particularly relevant in elderly patients, who may experience symptoms well below their theoretical maximal exercise capacity. With the 6MWT, a distance <350 m is associated with increased mortality in patients with HF, and change in walking distance >50 m is considered clinically relevant [5,6,7].

To our knowledge, information on improvement in physical functional capacity with sacubitril/valsartan, as assessed by the 6MWT, is still scant. In our daily practice, we apply this test to all patients whenever possible; therefore, we report here the findings observed in a small series of 5 patients with HFrEF after a 1-month treatment with sacubitril/valsartan at full dose.

Case Descriptions

Table 1 summarizes the clinical information of all patients at baseline and after 1 month of sacubitril/valsartan therapy at full dose, whereas Figure 1 displays information on the 6MWT. The mean distance walked on the 6MWT at baseline was 129 m (±64), and this value increased to 436 m (±156) after 1 month of therapy with sacubitril/valsartan 97/103 mg b.i.d. The mean difference from baseline was 305 m (±110). A short description of all cases is provided below.

Table 1

Clinical information of all patients at baseline and after 1 month of therapy with sacubitril/valsartan at full dose

/WebMaterial/ShowPic/912430

Fig. 1

Distance walked on the 6-min walk test at baseline and after 1 month of therapy with sacubitril/valsartan at full dose.

/WebMaterial/ShowPic/912429

Case 1

Case 1 is an 87-year-old woman with NYHA class III HF, left ventricular ejection fraction of 32%, atrial fibrillation, and a prior STEMI. She was receiving ramipril 2.5 mg/day. After washout, she was switched to sacubitril/valsartan at a starting dose of 24/26 mg b.i.d. for 2 weeks. After 2 weeks, the dosage was titrated to 49/51 mg b.i.d. for 3 weeks, and then to 97/103 mg b.i.d. After 1 month of sacubitril/valsartan 97/103 mg b.i.d., the NHYA class had decreased to I/II, left ventricular ejection fraction improved by 10% and, overall, the patient experienced a >200-m improvement in the 6MWT.

Case 2

Case 2 is a 72-year-old man with two prior STEMIs who had HF with NHYA class III with an implantable cardioverter defibrillators. He was able to walk 80 m on the 6MWT. Before the initiation of sacubitril/valsartan, he was on valsartan 80 mg/day; he was then switched to the ARNi, titrated gradually over time (2 weeks at 24/26 mg b.i.d., 3 weeks at 49/51 mg b.i.d., and then full dose). After 1 month of therapy with sacubitril/valsartan, his NHYA class decreased to II and he could walk 420 m on the 6MWT.

Case 3

Case 3 is a male, 67 years old, with idiopathic dilated cardiomyopathy and HF, NHYA class III. After starting treatment with ramipril 2.5 mg/day, he was switched to sacubitril/valsartan. The dosage of this ARNi was titrated as follows: 2 weeks at 24/26 mg b.i.d., 4 weeks at 49/51 mg b.i.d., and then 97/103 mg b.i.d. After 1 month of sacubitril/valsartan at full dose, his NHYA class decreased to I/II and the patient showed a 4-fold improvement in the distance walked on the 6MWT (baseline: 126 m; 1 month: 510 m).

Case 4

This 68-year-old woman presented with a recent STEMI and NHYA class II/III HF. She was able to walk 220 m on the 6MWT. After a period on ramipril 2.5 mg/day, treatment with sacubitril/valsartan was started (24/26 mg b.i.d. for 2 weeks, 49/51 mg b.i.d. for 2 weeks, and then 97/103 mg b.i.d.). After 1 month on the full dosage of the ARNi, her NHYA class had decreased to I/II and she had almost tripled the distance on the 6MWT (640 m).

Case 5

Case 5 is an elderly male (88 years) with idiopathic dilated cardiomyopathy and class III NHYA. His distance on the 6MWT was only 60 m. In this patient, titration of sacubitril/valsartan after ramipril treatment was slower than for the other patients of this case series (4 weeks at 24/26 mg b.i.d., 4 weeks at 49/51 mg b.i.d., and then full dose). In addition, this subject showed a decrease in NHYA class to I/II and a marked increase in the distance walked on the 6MWT.

Discussion

The introduction of sacubitril/valsartan therapy has undoubtedly represented a major breakthrough in the treatment of HF [8]. In this small case series, the efficacy of this compound in the treatment of HF was further confirmed in a “real life” setting: all patients showed, after only 1 month of therapy, at full dose optimization (97/103 mg b.i.d.) a reduction in NHYA class, which was paralleled by increased left ventricular ejection fraction and decreased concentration of NT-proBNP. Blood pressure and estimated glomerular filtration rate were overall unchanged with respect to values reported at the initiation of this therapy.

In particular, we focused our attention on physical capability, as assessed by the 6MWT, a simple test which can accurately reproduce daily activities and, therefore, has a major value in the comprehensive assessment of HF patients. To our knowledge, this is the first report investigating the results of the 6MWT in a “field practice” scenario.

Although our findings can be considered in a setting of a clinical series, after 1 month of therapy with sacubitril/valsartan optimized at full dose, we observed in all cases a remarkable increase in the distance walked on the 6MWT - well above the 50-m threshold which is considered clinically relevant for HF patients [5,6,7]. Moreover, 4 out of 5 patients were able to walk for >350 m, which is important as mortality is higher in HF patients who score below this threshold.

These results need further confirmation in prospective well-conducted studies. Meanwhile, according to our preliminary findings, a 1-month therapy with sacubitril/valsartan at a 97/103-mg b.i.d. dose appears to be associated with a relevant improvement on the 6MWT, with a potential impact on improvement of daily activities for HF patients and better quality of life.

Acknowledgements

Editorial assistance for the preparation of this paper was provided by Luca Giacomelli, PhD, on behalf of Content Ed Net; this assistance was supported by Novartis.

Conflict of Interest

The authors have no conflict of interest directly relevant to this study.


References

  1. Langenickel TH, Dole WP: Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today Ther Strategy 2012;9:e131-e139.
    External Resources
  2. McMurray JJV, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  3. Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai A, Shi VC, Lefkowitz MP, McMurray JJV: Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial. JACC Heart Fail 2017;5:471-482.
  4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891-975.
  5. Rostagno C, Gensini GF: Six minute walk test: a simple and useful test to evaluate functional capacity in patients with heart failure. Intern Emerg Med 2008;3:205-212.
  6. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE: The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J 2009;39:495-501.
  7. Du H, Wonggom P, Tongpeth J, Clark RA: Six-min walk test for assessing physical functional capacity in chronic heart failure. Curr Heart Fail Rep 2017;14:158-166.
  8. Latini R, Masson S, Staszewsky L: Heart failure trials on pharmacological therapy in 2015: lessons learned and future outlook. Expert Rev Cardiovasc Ther 2016;14:703-11.

Author Contacts

Luca Sgorbini

Unit of Cardiac Rehabilitation, ASL RM 1

Villa Betania, Via Pio IV, 42

IT-00165 Rome (Italy)

E-Mail Sgorbini.luca@libero.it


Article / Publication Details

First-Page Preview
Abstract of  

Published online: December 21, 2017
Issue release date: December 2017

Number of Print Pages: 4
Number of Figures: 1
Number of Tables: 1

ISSN: 0008-6312 (Print)
eISSN: 1421-9751 (Online)

For additional information: https://www.karger.com/CRD


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References

  1. Langenickel TH, Dole WP: Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today Ther Strategy 2012;9:e131-e139.
    External Resources
  2. McMurray JJV, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees: Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  3. Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai A, Shi VC, Lefkowitz MP, McMurray JJV: Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial. JACC Heart Fail 2017;5:471-482.
  4. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 2016;18:891-975.
  5. Rostagno C, Gensini GF: Six minute walk test: a simple and useful test to evaluate functional capacity in patients with heart failure. Intern Emerg Med 2008;3:205-212.
  6. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE: The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J 2009;39:495-501.
  7. Du H, Wonggom P, Tongpeth J, Clark RA: Six-min walk test for assessing physical functional capacity in chronic heart failure. Curr Heart Fail Rep 2017;14:158-166.
  8. Latini R, Masson S, Staszewsky L: Heart failure trials on pharmacological therapy in 2015: lessons learned and future outlook. Expert Rev Cardiovasc Ther 2016;14:703-11.